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The experimental approach, based on U-M research, delivers two different genes directly into the brains of patients following the operation to remove the bulk of their tumors.

The idea: trigger immune activity within the brain itself to kill remaining tumor cells — the ones neurosurgeons can’t take out, which make this type of tumor so dangerous.

It’s the first time this gene therapy approach is being tried in humans, after more than a decade of research in experimental models.

One of the genes is designed to kill tumor cells directly, and is turned on when the patient takes a certain drug. The other gene spurs the body’s own immune system to attack remaining cancer cells. Both are delivered into brain cells via a harmless virus.

The Phase I clinical trial has already enrolled two patients who have tolerated the gene delivery without complications. All patients in the study must have a presumptive diagnosis of WHO grade 3 or 4 malignant primary glioma, such as glioblastoma multiforme; patients must not have been treated yet by any therapy. They must also meet other criteria for inclusion in the trial.

More patients will be able to enroll at a pace of about one every three weeks, through a careful selection process. In addition to surgery and gene therapy at U-M, each will receive standard chemotherapy and radiation therapy as well as follow-up assessments for up to two years.

“We’re very pleased to see our years of research lead to a clinical trial, because based on our prior work we believe this combination of cell-killing and immune-stimulating approaches holds important promise,” says principal investigator Pedro Lowenstein, M.D., Ph.D., the U-M Medical School Department of Neurosurgery professor who has co-led the basic research effort to develop and test the strategy.

Co-leader Maria Castro, Ph.D., notes that the patients who agree to take part in the Phase I trial will be the first in the world to help establish the safety of the approach in humans. “Without them, and without our partners on the U-M Neurosurgery team, and donors to the Phase One Foundation that support our work, we wouldn’t be able to take this important step in testing this novel therapeutic approach.”

Patients who feel anxious and uneasy with their doctor may be impacted the most. “Anxiously attached patients may experience and report more physical and emotional problems when the relationship with their physician is perceived as less trusting,” said Chris Hinnen, Ph.D., lead author and clinical psychologist at Slotervaart Hospital in Amsterdam, The Netherlands.

The researchers acknowledge that the issue of trust between patients and their doctors can be complicated, but observe that it’s important to understand fears of rejection and abandonment that often exist in anxiously attached patients.

Hinnen and his colleagues analyzed questionnaire responses from 119 participants with breast, cervical, intestinal or prostate cancers at 3, 9 and 15 months after their diagnosis. Seventy-one percent of those surveyed were female and had an average age of 59 years old. Researchers used a shortened version of the Wake Forest Physician Trust Scale and the Revised Experiences in Close Relationships scale to determine 1) participants’ trust in the physician most involved in treatment and 2) participants’ attachment anxiety or avoidance at the 3 month mark and assessed their distress and physical limitations at three sequential time intervals. Lower levels of trust were associated with more distress at all periods and more physical limitations at three and nine months for anxiously-attached patients.

“In some people, early childhood experiences coupled with constitutional factors have led to an exaggerated desire for closeness and intimacy together with a high fear of rejection and abandonment,” Hinnen noted. “Consequently, the feeling of not being able to rely on one’s physician may be especially frightening and stressful for anxiously attached patients.” People with less attachment anxiety may have better ways of coping with a less trusting physician relationship.

Michelle B. Riba, M.D., professor and associate chair for Integrated Medical and Psychiatric Services at the University of Michigan, noted doctor-patient relationships are very important, especially when the patient is confronted with cancer. “However, this study was not free from bias because it was primarily comprised of women who liked their doctors, and these women were already in a personal relationship which portended an attachment to a relationship with their physician.”

Riba also noted the three-month time line when cancer patients in the study were asked about doctor-patient trust levels. “The problem is at three-months patients may be seeing a variety of physicians such as a surgeon, oncologist, medical oncologist or radiologist, not just one doctor,” she said.

The study notes that it is important to take into account the fact that some patients don’t feel connected to their doctor. These patients may be more at risk for emotional and physical adjustment problems associated with cancer diagnosis and treatment.

Riba added, “As physicians we try to place patients with doctors that match a patient’s style, but that doesn’t always happen. Instead, patients may move and look for other relationships on their own.”

“Since the patient-physician relationship has such an impact on patient well-being,” Hinnen said, “especially for those who are most vulnerable, limiting free choice of a [cancer] physician seems foolish.”